This application addresses broad Challenge Area 11: Regeneration and specific topic challenge topic 11-DK-105: Transdifferentiation or directed reprogramming of one cell fate to another (e.g., a pancreatic exocrine cell to a pancreatic beta cell). In 2005, rates of pre-diabetes/diabetes approached 40% in the US and this number is projected to rise. Current therapies are inadequate: we cannot prevent the death of beta cells in type II diabetics and pancreas transplant is available to very little type I diabetics. Therefore, the ability to regenerate or preserve the pancreatic beta cell would make an immense clinical impact. The study of the insulin promoter has led to such novel therapies. In mice, the ectopic expression of 3 transcription factors that activate the insulin promoter can convert pancreatic exocrine cells into insulin producing endocrine cells. These intriguing findings show that a program of beta cell differentiation can be co-opted for therapeutic use and that the insulin promoter is a necessary part of this program. We propose to find these new targets for beta cell regeneration and preservation by performing whole genome RNA interference (RNAi) screen for regulators of the insulin promoter in pancreatic beta cells. We have developed a statistically robust, high throughput RNAi screening system for insulin promoter activity and have already begun to identify novel hits. We will complement this functional data set with deep sequencing of the beta cell transcriptome. Finally, we will confirm our hits in vivo using transgenic RNAi mice. This collaborative proposal brings together the resources of a lab with expertise in RNA interference and an immediately adjacent lab with expertise in beta cell biology. At the end of the grant period, we anticipate the identification of at least several novel insulin promoter regulators that will not only heighten our understanding of beta cell biology but will also serve as novel drug targets for diabetes treatment. PUBLIC HEALTH RELEVANCE: In 2005, nearly 40% of the US population had diabetes or pre-diabetes - diseases caused by insulin deficiency. We propose to identify genes that regulate insulin production by the pancreatic beta cell. We hope that these genes could be targets for new diabetes therapies.